Obesity and its associated disorders are common and very serious public health problems in the United States and throughout the world. Upper body obesity is the strongest risk factor known for type 2 diabetes mellitus and is a strong risk factor for cardiovascular disease. Obesity is a recognized risk factor for hypertension, atherosclerosis, congestive heart failure, stroke, gallbladder disease, osteoarthritis, sleep apnea, reproductive disorders such as polycystic ovarian syndrome, cancers of the breast, prostate, and colon, and increased incidence of complications of general anesthesia.
Obesity reduces life-span and carries a serious risk of the co-morbidities listed above, as well disorders such as infections, varicose veins, acanthosis nigricans, eczema, exercise intolerance, insulin resistance, hypertension hypercholesterolemia, cholelithiasis, orthopedic injury, and thromboembolic disease (Rissanen et al., Br. Med. J. 301:835-837 (1990)). Obesity is also a risk factor for the group of conditions called insulin resistance syndrome, or “Syndrome X” and metabolic syndrome. The worldwide medical cost of obesity and associated disorders is enormous.
Obesity remains a poorly treated, chronic, essentially intractable metabolic disorder. Accordingly, a need exists for new therapies useful in weight reduction and/or weight maintenance in a subject. Such therapies would lead to a profound beneficial effect on the subject's health.
The present invention provides methods and compositions useful in the control, treatment, and prevention of obesity and obesity-related conditions, disorders, and diseases, such as those referenced above.
Pancreatic polypeptide ((PP) is a member of the PP-fold family of peptides which also includes neuropeptide Y (NPY) and peptide YY (PYY). PP is an endogen-ously secreted 36 amino acid, C-terminally amidated peptides, which is characterized by a three-dimensional structure, the PP-fold, which is shared by NPY and PYY.
PP is released from endocrine cells in pancreatic islets, almost exclusively governed by vagal cholinergic stimuli elicited especially by food intake. PP has various effects on the gastrointestinal tract, but none of these are observed in isolated cells and organs, and all appear to be dependent on an intact vagal nerve supply. PP simulates Y4 receptors located in the periphery and in the brain. In the brain, there is a strong expression of Y4 receptors in the nucleus tractus solitarirus (NTS), the activation of which results in the effects of PP as a satiety hormone. The effect of PP on food intake may be mediated through an action on neurons, especially the POMC/CVART neurons in the arcuate nucleus.
There are four well established types of NPY receptors in man; Y1, Y2, Y4 and Y5, which all recognize NPY1-36 and PYY1-36 with similar affinity. In contrast PP demonstrates selectivity among the NPY receptor subtypes having subnanomolar affinity for the Y4 receptor.
PP and related analogs have been suggested for use in the treatment of obesity and associated diseases, including for example, Prader Willi's syndrome, based on the demonstrated effects of certain of these peptides in animal models and in man. Additionally obese subjects have been shown to have low basal levels of PP and lower secreted levels in response to a meal. High PP levels are found in patients with anorexia nervosa.
Since the mid 1970's it has been shown that PP reduces food intake in rodents. Studies have demonstrated that after peripheral administration to animals, PP is a powerful and efficient anorexigenic agent. Later it was shown that PP has no effect on food intake and appetite in Y4 receptor knock-out mice, strongly suggesting that PP's actions on food intake are through it's interactions with the Y4 receptor. PP has also been shown to have an effect on food intake in diet induced obese animals.
PP has been found to reduce food intake in humans. In 1993, it was reported that infusion of PP in morbidly obese patients with Prader Willi's syndrome decreased food intake. In a subsequent study, infusion of PP in normal human subjects showed a long lasting suppression of appetite and reduced food intake over 24 hours.
PP has a short circulating half-life in humans limiting its use as a therapeutic agent. For the treatment of conditions responsive to Y4 receptor modulation, such as obesity, diabetes and intestinal hypersecretion, it would be desirable to have a more druggable molecule with better pharmacokinetics, selectivity and potential for oral delivery.
In particular, it would be highly desirable to use such agents which are selective for the Y4 receptor over the Y1 receptor. This is particularly important since activation of the Y1 receptor is expected to potentially cause unwanted cardiovascular and renal side effects such as vasoconstriction and natriuresis.
Thus, use of selective and efficacious Y4 receptor agonists over Y1 receptor agonists would be particularly useful in diseases and conditions susceptible to Y4 receptor activation.
The present invention relates to novel substituted diaminocyclohexane compounds which have the ability to activate, partially activate and/or modulate the NPY Y4 receptor. Such compounds are therefore potentially useful for the treatment or prophylaxis of obesity, to control appetite, feeding, food intake, energy expenditure, caloric intake, gastric motility, diabetes and other related conditions.